Methylmercury (MeHg) is a ubiquitous environmental pollutant. The neurotoxicity of MeHg and the high susceptibility of the developing brain are well established both in humans and experimental animals. Prenatally exposed children display a range of effects varying from severe cerebral palsy to subtle developmental delays. Many of the more subtle effects of developmental MeHg exposure can be permanent, including behavioral abnormalities and loss of IQ, and impart a significant cost to society as a whole. It is estimated that as many as 15% of American women of childbearing age have total blood mercury concentrations at a level above that associated with loss of IQ (>3.5 <g/L) in their children. Recently, genetic polymorphisms in glutathione-related genes have been associated with higher blood mercury levels which suggests that these polymorphisms may play a role in the susceptibility to MeHg-induced neurodevelopmental dysfunction. We have designed a strategy to determine the functional role of polymorphisms in glutathione S-transferase pi 1, glutamate-cysteine ligase catalytic subunit, and glutamate-cysteine ligase modifier subunit (GSTP1, GCLC and GCLM, respectively) in susceptibility to MeHg-induced neurodevelopmental dysfunction using humanized zebrafish. We have previously demonstrated that zebrafish exposed during development to low-to-moderate levels of MeHg show neurological deficits, during development and as adults, similar to those seen in humans. This laboratory model will allow us to efficiently explore gene-environment interactions and the role of specific gene variants individually and in combination. If the genetic polymorphisms we are investigating are shown to influence sensitivity to developmental MeHg, the societal impact of MeHg exposures may be dramatically underestimated. PUBLIC HEALTH RELEVANCE: Methylmercury (MeHg) is a ubiquitous environmental pollutant. The neurotoxicity of high levels of MeHg and the increased susceptibility of the developing brain are well established both in humans and experimental animals. Prenatally exposed children display a range of effects varying from severe cerebral palsy to subtle developmental delays (Castoldi et al., 2001). Many of the more subtle effects of developmental MeHg exposure can be permanent, including behavioral abnormalities and loss of IQ. It is estimated that as many as 15% of American women of childbearing age have total blood mercury concentrations at a level above that associated with loss of IQ (>3.5 <g/L) in their children. As a result, as many as 637,233 children are born each year with cord blood mercury levels above that which is associated with loss of IQ (Trasande et al., 2005). The associated loss of productivity in the United States is estimated to be greater than $8 billion annually (Trasande et al., 2005). If the genetic polymorphisms we are investigating prove to influence sensitivity to developmental MeHg, the societal impact may be dramatically underestimated.